P1201: ZANUBRUTINIB PLUS RCHOP(ZR-CHOP) REGIMEN ACHIEVES HIGH COMPLETE RESPONSE RATE IN THE TREATMENT OF NEWLY-DIAGNOSED DOUBLE-EXPRESSION DIFFUSE LARGE B CELL LYMPHOMA
Authors: Q. He, L. Xie, R. Zhao, J. Ma, C. Liu, C. Chen, H. Wang, K. Lu, J. Li, C. Zhao, N. Shan, L. Xing, Z. Li
Journal: HemaSphere (2022)

Background: Diffuse large B cell lymphoma with double expression of MYC/BCL2(DE-DLBCL), is usually responsive poorly to standard therapy of R-CHOP regimen, and the long-term survival rate of patients with DE-DLBCL is only 30% - 40%. Recently, Phoenix study demonstrate Ibrutinib plus R-CHOP improved EFS and OS (versus placebo plus R-CHOP) for DE-DLBCL younger patients. While for elder patients, the outcome makes no difference between two groups, due partly to the poor tolerance in Ibrutinib group. The novel BTK inhibitor, zanubrutinib, have better safety profile. So we suppose zanubrutinib plus R-CHOP (ZR-CHOP) may improve the outcome of DE-DLBCL even in older patients. Aims: To investigate the response rate, progression free survival (PFS) and safety of Zanubrutinib plus RCHOP (ZR-CHOP) regimen in the first-line treatment of DE-DLBCL patients. Methods: We initiate a prospective, single arm, phase II clinical trial. Standard dose of Zanubrutinib plus R-CHOP regimen (ZR-CHOP) was adopted in our center as first-line treatment for patients (18-75yrs) with DE-DLBCL. DE-DLBCL is defined as ≧40% positive rate for MYC and ≧50% for BCL2 by immunohistochemistry, and double hit cases were excluded through FISH test (MYC, BCL2 and BCL6). The patients in Ann Arbor stage I were also excluded. The 6 cycles of ZR-CHOP plus 2R were administered as induction therapy, with no maintenance. The primary endpoint was two-year-PFS. Response was assessed after 2 cycles of therapy using CT scanning, and after 4 and 6 cycles of therapy using PET-CT. Results: From November 6, 2020 to February 16, 2022, 28 patients with DE DLBCL were enrolled and completed 6 cycles of ZR-CHOP regimen therapy. The baseline characteristics of the patients are listed in Table 1. After 2 cycles of therapy, 2/28 patients achieved CR (7.1%), 25/28 PR (89.3%) and 1/28 not evaluated. After 4 cycles of therapy, 23/28 got CR (82.1%), 3/28 PR (10.7%), and 2/28 PD (7.1%). After 6 cycles of therapy, 24/28 CR (85.7%), and 4/28 PD (14.3%) (Figure 1). The response rate after 6 cycles of ZRCHOP regimen was obviously higher than that of the previous report after R-CHOP regimen for DE-DLBCL (85.7%VS 70%). After median follow-up of 6 month (2-14m), the estimated PFS rate is 88.2%（95%,CI 81.7-94.7, Figure 2）.Totally four patients progressed during or shortly after the induction therapy. NGS analysis revealed 3/4 patients has the mutation of TP53, solely or with other cytogenetic disorders, and the other one has the mutation of ATM. All the four patients are still alive after second line therapy including CART therapy and auto-stem cell transplantation. About the safety of the study, grade 3 or more severe AEs were recorded in 15/28 patients (42.9% vesus 89.9% in PHOENIX study), including 12 patients with grade 3-4 hematological toxicities and 3 patients with pneumonia. No patients withdraw permanently from the study due to toxicity. No atrial fibrillation, tumor lysis syndrome or massive hemorrhage were reported. Image:Summary/Conclusion: Despite the small sample size and short time of follow-up, we found that ZR-CHOP regimen achieved very high CR rate for DE DLBCL, and the toxicities were acceptable, which may indicate a promising therapy for this subset of DLBCL. Further studies are required to prove the benefit of zanubrutinib when added to R-CHOP for newly-dignosed DE-DLBCL. TP53 mutation is probably the main reason for disease progression.